Background: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α 1 -adrenoceptors (α 1 -ARs). Inhibition of such an activity at α 1 -AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. Methods: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α 1 -AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α 1A /α 1B -α 1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α 1D -AR, that is the α 1 - AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. Results: We found that all the three benzodioxane-related α 1 -AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. Conclusions: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α 1 -AR antagonist is related neither to a particular profile of α 1 -AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α 1 -AR antagonists with L-type Ca 2+ channels.

Micucci, M., Chiarini, A., Budriesi, R. (2019). Neutral/negative α 1 -AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium. PHARMACOLOGICAL REPORTS, 71(1), 128-132 [10.1016/j.pharep.2018.10.007].

Neutral/negative α 1 -AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium

Micucci, Matteo;Chiarini, Alberto;Budriesi, Roberta
2019

Abstract

Background: Constitutive (agonist-independent) activity is a prerogative of many G protein-coupled receptors (GPCRs) including α 1 -adrenoceptors (α 1 -ARs). Inhibition of such an activity at α 1 -AR subtypes by antagonists with negative efficacy is difficult to be adequately tested. Methods: In the present experimental approach, we compared the activity of three calcium channel blockers (nifedipine, diltiazem and verapamil) and of three potent benzodioxane-based α 1 -AR antagonists, differing for subtype selectivity and inverse agonist properties, in producing smooth muscle relaxation and negative inotropy under the same test conditions. We selected, as benzodioxane derivatives, (S)-WB4101, inverse agonist with slight α 1A /α 1B -α 1D AR selectivity, and two previously developed analogues. Both of these are potent antagonists at α 1D -AR, that is the α 1 - AR subtype suspected of the highest susceptibility to inverse agonists for its high degree of basal activity, but only one is inverse agonist. Results: We found that all the three benzodioxane-related α 1 -AR antagonists have significant intrinsic relaxant activity on non-vascular smooth muscle and moderate negative inotropic effect, while they do not relax aorta. Their potency is always lower than that of three calcium channel blockers. Conclusions: Intrinsic myorelaxant and negative inotropic activity of the three benzodioxane-based α 1 -AR antagonist is related neither to a particular profile of α 1 -AR subtype selectivity nor to whether or not being an inverse agonist, but it parallels the calcium antagonists effects indicating a direct interaction of the three α 1 -AR antagonists with L-type Ca 2+ channels.
2019
Micucci, M., Chiarini, A., Budriesi, R. (2019). Neutral/negative α 1 -AR antagonists and calcium channel blockers at comparison in functional tests on guinea-pig smooth muscle and myocardium. PHARMACOLOGICAL REPORTS, 71(1), 128-132 [10.1016/j.pharep.2018.10.007].
Micucci, Matteo; Chiarini, Alberto; Budriesi, Roberta*
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/675846
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